Triple-Negative Breast Cancers (TNBC = negative on clinical assays for ER, PR and HER2) are among the most clinically challenging because of their inherent aggressive biology and lack of treatment options (typically limited to chemotherapy only). These tumors are also more common in young African American women, thus contributing to racial disparities and mortality. To advance our knowledge of the biology of TNBC, we believe it critical to precisely define the biological entities that are present within this known heterogeneous group, to next determine their driving biology, and to lastly employ robust biomarkers for defining more homogeneous subgroups of TNBC for pairing with the appropriate targeted drug(s). We hypothesize that TNBC are composed of two main biologically distinct groups (i.e. Basal-like and Claudin-low subtypes), and that the best way to make therapeutic advances is to comprehensively study these subtypes to identify their unique and potentially targetable molecular features. We hypothesize that a high proportion of Basal-like breast cancers have evidence of a DNA repair deficiency caused by either loss of BRCA1/2, or loss of chromosome 5q, which contains many genes crucial to DNA repair (RAD17, RAD50, UIMC1). Conversely, Claudin-low tumors do not share these defects, but have unique properties including an active immune infiltrate and evidence of epithelial-to-mesenchymal transition. We will test the hypothesis that DNA repair defects, and differences in growth factor signaling pathways, can be used to therapeutically target TNBC by 1) using multiple validated pre-clinical murine models and primary human tumor xenografts, and testing promising new targeted agents (PARP inhibitors, PIKSCA inhibitors and MEK inhibitors), 2) combinations of these agents, and combinations with DNA-damaging chemotherapuetics (carboplatin), and 3) by studying tumor samples from 4 randomized neoadjuvant clinical trials testing carboplatin and/or ABT- 888 in TNBC patients with the hypothesis that these DNA damage-inducing agents will be particularly effective on tumors that have a profound DNA repair defect. We will perform gene expression profiling and DNA copy number analyses to test pre-defined genomic signatures and copy number changes as markers of responsiveness, and for de novo profile discovery. Our across-species comparative biology approach merges pre-clinical models with human clinical trials, and if successful, we will identify new targeted agents for TNBC along with companion diagnostics.